Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

Vigo Heissmeyer, Fernando Macián, Sin Hyeog Im, Rajat Varma, Stefan Feske, K. Venuprasad, Hua Gu, Yun Cai Liu, Michael L. Dustin, Anjana Rao

Research output: Contribution to journalArticle

413 Citations (Scopus)

Abstract

Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-θ and PLC-γ1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalNature Immunology
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

Fingerprint

Calcineurin
Proteolysis
T-Lymphocytes
Proteins
Immunological Synapses
Calcium
Lymphocyte Function-Associated Antigen-1
Calcium Signaling
Ubiquitin
Cell Adhesion
Signal Transduction
Transcription Factors
Antigens
Messenger RNA
Membranes
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. / Heissmeyer, Vigo; Macián, Fernando; Im, Sin Hyeog; Varma, Rajat; Feske, Stefan; Venuprasad, K.; Gu, Hua; Liu, Yun Cai; Dustin, Michael L.; Rao, Anjana.

In: Nature Immunology, Vol. 5, No. 3, 01.03.2004, p. 255-265.

Research output: Contribution to journalArticle

Heissmeyer, V, Macián, F, Im, SH, Varma, R, Feske, S, Venuprasad, K, Gu, H, Liu, YC, Dustin, ML & Rao, A 2004, 'Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins', Nature Immunology, vol. 5, no. 3, pp. 255-265. https://doi.org/10.1038/ni1047
Heissmeyer, Vigo ; Macián, Fernando ; Im, Sin Hyeog ; Varma, Rajat ; Feske, Stefan ; Venuprasad, K. ; Gu, Hua ; Liu, Yun Cai ; Dustin, Michael L. ; Rao, Anjana. / Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. In: Nature Immunology. 2004 ; Vol. 5, No. 3. pp. 255-265.
@article{9e4fd9c4a1ce481dbf7404a205c00aa8,
title = "Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins",
abstract = "Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-θ and PLC-γ1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.",
author = "Vigo Heissmeyer and Fernando Maci{\'a}n and Im, {Sin Hyeog} and Rajat Varma and Stefan Feske and K. Venuprasad and Hua Gu and Liu, {Yun Cai} and Dustin, {Michael L.} and Anjana Rao",
year = "2004",
month = "3",
day = "1",
doi = "10.1038/ni1047",
language = "English (US)",
volume = "5",
pages = "255--265",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

AU - Heissmeyer, Vigo

AU - Macián, Fernando

AU - Im, Sin Hyeog

AU - Varma, Rajat

AU - Feske, Stefan

AU - Venuprasad, K.

AU - Gu, Hua

AU - Liu, Yun Cai

AU - Dustin, Michael L.

AU - Rao, Anjana

PY - 2004/3/1

Y1 - 2004/3/1

N2 - Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-θ and PLC-γ1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.

AB - Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-θ and PLC-γ1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.

UR - http://www.scopus.com/inward/record.url?scp=12144290293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12144290293&partnerID=8YFLogxK

U2 - 10.1038/ni1047

DO - 10.1038/ni1047

M3 - Article

C2 - 14973438

AN - SCOPUS:12144290293

VL - 5

SP - 255

EP - 265

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 3

ER -